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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0536v1 202/2/249    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Ramanjaneya, M. Articles by Randeva, H. PubMed PubMed Citation Articles by Ramanjaneya, M. Articles by Randeva, H.

M Ramanjaneya, Coventry, United Kingdom
A Conner, Coventry, United Kingdom
J Chen, Coventry, United Kingdom
P Kumar, Coventry, United Kingdom
J Brown, Coventry, United Kingdom
O Joehren, LÃÂbeck, Germany
H Lehnert, Lübeck, Germany
P Stanfield, Coventry, United Kingdom
H Randeva, coventry, cv4 7al, United Kingdom

Correspondence: Hs Randeva, Email: hrandeva{at}bio.warwick.ac.uk

Orexins A and B are neuropeptide hormones found throughout the CNS and periphery. They are required for a host of physiological processes including MAPK regulation, steroidogenesis, appetite control and energy regulation. Whilst some signalling mechanisms have been proposed for individual recombinant orexin receptors in generic mammalian cell types, it is clear that the peripheral effects of orexin are spatially and temporally complex. This study dissects the different G-protein signalling and MAPK pathways activated in a pluripotent human adrenal H295R cell-line capable of all of the physiological steps involved in steroidogenesis. Both ERK1/2 and p38 were phosphorylated rapidly with a subsequent decline, in a time- and dose-dependent manner, in response to both orexin A and orexin B. Conversely there was little or no direct activation of the ERK5 or JNK pathways. A comprehensive analysis using signalling and MAPK inhibitors as well as receptor-specific antagonists determined the precise mediators of the orexin response in these cells. Both ERK1/2 and p38 activation were predominantly Gq- and to a lesser extent Gs-mediated; p38 activation even had a small Gi-component. Effects were broadly comparable for both orexin sub-types ORA and ORB and although most of the effects were transmitted through the OX1 receptor sub-type, we did observe a role for OX2R-mediated activation of both ERK1/2 and p38. Cortisol secretion also differed in response to ORA and ORB. These data suggest multiple roles for orexin-mediated MAPK activation in an adrenal cell-line, this complexity may help explain the diverse biological actions of orexins with wide-ranging consequences for our understanding of the mechanisms initiated by these steroidogenic molecules.

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				J. Wenzel, N. Grabinski, C. A. Knopp, A. Dendorfer, M. Ramanjaneya, H. S. Randeva, M. Ehrhart-Bornstein, P. Dominiak, and O. Johren Hypocretin/orexin increases the expression of steroidogenic enzymes in human adrenocortical NCI H295R cells Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2009; 297(5): R1601 - R1609. [Abstract] [Full Text] [PDF]